1. Field of the Invention
The present invention relates to macrocyclic depsipeptides, including didemnin and tamandarin analogs and fragments thereof, which are useful as anti-cancer agents and for other purposes. Methods of using these compounds as inhibitors of protein synthesis, cell growth, tumorigenesis, and viral infection, and for immunosuppresive therapy, and as enhancers of apoptosis are also provided. Methods of making the tamandarin analogs are also provided.
2. Background Art
Tamandarins A and B are naturally occurring didemnin analogs which have been isolated from a marine tunicate. Tamandarins A and B belong to a family of compounds (didemnins—from organisms of the Didemnidae family) which potently inhibit protein synthesis and cell cycle progression and induce rapid apoptosis (Grubb et al., Biochem. Biophys, Res. Commun. 215:1130-1136 (1995); Johnson et al., FEBS Lett. 383:1-5 (1996); Johnson et al., Immunol. Cell Biol. 77:242-248 (1999); Johnson et al., J. Cell. Biochem. 72:269-278 (1999)). Other didemnins, including didemnin B, didemnin M, and dehydrodidemnin B, exhibit cytotoxic and cytostatic effects as well.
Tamandarins A and B exhibit biological activity which is similar to the activities exhibited by didemnin B. See, e.g., Liang, et al., J. Am. Chem. Soc. 123:4469-4474 (2001). For example, tamandarin A is a potent inhibitor of protein synthesis, cell growth, and tumorigenesis. Tamandarin A exhibits significant in vitro activity against pancreatic carcinoma (Liang et al., Org. Lett. 1: 1319-1322 (1999)).
A significant limitation on the use of the tamandarins and didemnins, either for research or for other applications, is the limited supply of tamandarins that is available from natural sources and the difficulty and expense of isolating these compounds. A need exists for a method of synthesizing tamandarins A and B and other didemnin analogs.
Furthermore, very few derivatives or analogs of tamandarins A and B have been prepared and examined. Additional derivatives and analogs of tamandarins A and B and didemnins are needed. Additionally, compound which are useful in the synthesis of tamandarins and didemnins are needed. Additional compounds that are useful as inhibitors of protein synthesis, cell growth, tumorigenesis, and viral infection, and for immunosuppresive therapy, and/or as enhancers of apoptosis are also needed.